P-007: HYDROXYUREA FOR THE MANAGEMENT OF SICKLE CELL DISEASE IN LOW- AND MIDDLE-INCOME COUNTRIES: A SYSTEMATIC REVIEW (2000–2022)
Authors: TSHILOLO L., MARFO K., ADISON F., KHAN S., PAINTSIL V.
Journal: HemaSphere (2022)

Purpose: Hydroxyurea (HU) is a disease modifying oral therapy with demonstrated clinical efficacy and safety in patients with sickle cell disease (SCD) for over 30 years. In low- and middle-income countries (LMICs) where the disease burden is high, universal HU treatment is limited. Our aim for this systematic literature review was to summarise the available evidence conducted in low-resource settings on HU efficacy, safety and real-world effectiveness to demonstrate the need for wider access to HU for SCD patients in LMICs. The preliminary observations from clinical studies are presented here. Materials and methods: Articles published in Embase, PubMed, OVID and Web of Science between January 2000–2022 were reviewed; studies assessing the impact of HU in patients with SCD were considered. Results: Out of 3709 screened articles, 124 unique studies were included (Figure) with 20 clinical trials. Majority of the studies are from sub-Saharan Africa (SSA) and Latin America. The initial dose of HU ranged from 10–25 mg/kg/day and the most common initial dose was 15–20 mg/kg/day; the maximum tolerated dose (MTD) was 25–35 mg/kg/day. Across various age groups, as anticipated, a significant increase in haemoglobin, foetal haemoglobin and mean corpuscular volume levels with HU at both fixed (20 mg/kg/day) and escalated dose (≤35 mg/kg/day). HU at doses 15–30 mg/kg/day reduced the need for transfusions during the treatment period. HU treatment initiation reduced VOC-related pain, and reduction was better with escalated (30 mg/kg/day) versus fixed dosing (20–25 mg/kg/day). Similar reductions across various age groups were observed for atherosclerotic events. Initial low-dose HU therapy of 10 mg/kg/day and a 12-month MTD of 24.1±6.0 mg/kg/day reduced the primary stroke risk. Secondary strokes were prevented with HU (3 years; initial dose: 15–20 mg/kg/day; MTD: 30–35 mg/kg/day), and long-term treatment (3.5–9.3 years; 30–40 mg/kg/day) prevented recurrent strokes. HU treatment showed a reduction in the rates of hospitalisation, and this was?50% lower with escalated dose (29.0±3.5 mg/kg/day) when compared to fixed dose (19.3±1.7 mg/kg/day). Treatment with HU was also associated with significant reduction in malaria events and related hospitalisations. Significant reduction in the risk of mortality was observed after treatment with HU, assessed as events per 100 patients/person years, which can be attributed to fewer SCD–related clinical complications, infections, malaria and possibly transfusions. Various dosing of HU was well tolerated in children and adults, and the reported events of myelosuppression were mostly transient. Conclusion: Our preliminary observations suggest that clinical use of HU in low-resource settings is effective in improving haematological outcomes, reducing the risk of VOCs and primary and recurrent strokes, and reduction of malaria-related events. Need for transfusion, rates of hospitalisation and mortality were also reduced with HU treatment. These findings are in line with current consensus guidelines to initiate HU therapy to SCD patients starting as early as 9 months of age. We expect that the complete analysis of this systematic review will enable us to compile sufficient evidence for optimising the use of HU in LMICs.K. MARFO declares a conflict of interest: Stock shareholder: Novartis Other: Employee of Novartis S. KHAN declares a conflict of interest: Other: I am an employee of Novartis